tbuckley/cabot-search huggingface dataset:
Single-cell RNA-sequencing atlas reveals an FABP1-dependent immunosuppressive environment in hepatocellular carcinoma
Authors: Weiwei Tang, Guangshun Sun, Gu-Wei Ji, Tingting Feng, Qian Zhang, Hengsong Cao, Wenhao Wu, Xiaoyi Zhang, Chuan Liu, Hanyuan Liu, Tian Huang, Li Liu, Yongxiang Xia, Xuehao Wang
Journal: Journal for ImmunoTherapy of Cancer (2023)

Background Single-cell RNA sequencing, also known as scRNA-seq, is a method profiling cell populations on an individual cell basis. It is particularly useful for more deeply understanding cell behavior in a complicated tumor microenvironment. Although several previous studies have examined scRNA-seq for hepatocellular carcinoma (HCC) tissues, no one has tested and analyzed HCC with different stages. Methods In this investigation, immune cells isolated from surrounding normal tissues and cancer tissues from 3 II-stage and 4 III-stage HCC cases were subjected to deep scRNA-seq. The analysis included 15 samples. We distinguished developmentally relevant trajectories, unique immune cell subtypes, and enriched pathways regarding differential genes. Western blot and co-immunoprecipitation were performed to demonstrate the interaction between fatty acid binding protein 1 (FABP1) and peroxisome proliferator-activated receptor gamma(PPARG). In vivo experiments were performed in a C57BL/6 mouse model of HCC established via subcutaneous injection. Results FABP1 was discovered to be overexpressed in tumor-associated macrophages (TAMs) with III-stage HCC tissues compared with II-stage HCC tissues. This finding was fully supported by immunofluorescence detection in significant amounts of HCC human samples. FABP1 deficiency in TAMs inhibited HCC progression in vitro. Mechanistically, FABP1 interacted with PPARG/CD36 in TAMs to increase fatty acid oxidation in HCC. When compared with C57BL/6 mice of the wild type, tumors in FABP1–/– mice consistently showed attenuation. The FABP1–/– group’s relative proportion of regulatory T cells and natural killer cells showed a downward trend, while dendritic cells, M1 macrophages, and B cells showed an upward trend, according to the results of mass cytometry. In further clinical translation, we found that orlistat significantly inhibited FABP1 activity, while the combination of anti-programmed cell death 1(PD-1) could synergistically treat HCC progression. Liposomes loaded with orlistat and connected with IR780 probe could further enhance the therapeutic effect of orlistat and visualize drug metabolism in vivo. Conclusions ScRNA-seq atlas revealed an FABP1-dependent immunosuppressive environment in HCC. Orlistat significantly inhibited FABP1 activity, while the combination of anti-PD-1 could synergistically treat HCC progression. This study identified new treatment targets and strategies for HCC progression, contributing to patients with advanced HCC from new perspectives.
Chimeric antigen receptor T cells to target CD79b in B-cell lymphomas
Authors: Fuliang Chu, Jingjing Cao, Jingwei Liu, Haopeng Yang, Timothy J Davis, Shao-qing Kuang, Xiaoyun Cheng, Zheng Zhang, Swathi Karri, Long T Vien, Laura Bover, Ryan Sun, Francisco Vega, Michael Green, Richard Eric Davis, Sattva S Neelapu
Journal: Journal for ImmunoTherapy of Cancer (2023)

Chimeric antigen receptor (CAR) T cells targeting CD19 mediate potent and durable effects in B-cell malignancies. However, antigen loss or downregulation is a frequent cause of resistance. Here, we report development of a novel CAR T-cell therapy product to target CD79b, a pan B-cell antigen, widely expressed in most B-cell lymphomas.
Review and perspective on sleep-disordered breathing research and translation to clinics
Authors: Henri Korkalainen, Samu Kainulainen, Anna Sigridur Islind, María Óskarsdóttir, Christian Strassberger, Sami Nikkonen, Juha Töyräs, Antti Kulkas, Ludger Grote, Jan Hedner, Reijo Sund, Harald Hrubos-Strom, Jose M. Saavedra, Kristín Anna Ólafsdóttir, Jón S. Ágústsson, Philip I. Terrill, Walter T. McNicholas, Erna Sif Arnardóttir, Timo Leppänen
Journal: Sleep Medicine Reviews (2023)

Sleep-disordered breathing, ranging from habitual snoring to severe obstructive sleep apnea, is a prevalent public health issue. Despite rising interest in sleep and awareness of sleep disorders, sleep research and diagnostic practices still rely on outdated metrics and laborious methods reducing the diagnostic capacity and preventing timely diagnosis and treatment. Consequently, a significant portion of individuals affected by sleep-disordered breathing remain undiagnosed or are misdiagnosed. Taking advantage of state-of-the-art scientific, technological, and computational advances could be an effective way to optimize the diagnostic and treatment pathways. We discuss state-of-the-art multidisciplinary research, review the shortcomings in the current practices of SDB diagnosis and management in adult populations, and provide possible future directions. We critically review the opportunities for modern data analysis methods and machine learning to combine multimodal information, provide a perspective on the pitfalls of big data analysis, and discuss approaches for developing analysis strategies that overcome current limitations. We argue that large-scale and multidisciplinary collaborative efforts based on clinical, scientific, and technical knowledge and rigorous clinical validation and implementation of the outcomes in practice are needed to move the research of sleep-disordered breathing forward, thus increasing the quality of diagnostics and treatment.
Genome‐wide meta‐analysis and fine‐mapping prioritize potential causal variants and genes related to leprosy
Authors: Zhenzhen Wang, Tingting Liu, Wenchao Li, Gongqi Yu, Zihao Mi, Chuan Wang, Xiaojie Liao, Pengcheng Huai, Tongsheng Chu, Dianchang Liu, Lele Sun, Xi'an Fu, Yonghu Sun, Honglei Wang, Na Wang, Jianjun Liu, Hong Liu, Furen Zhang
Journal: MedComm (2023)

To date, genome-wide association studies (GWASs) have discovered 35 susceptible loci of leprosy; however, the cumulative effects of these loci can only partially explain the overall risk of leprosy, and the causal variants and genes within these loci remain unknown. Here, we conducted out new GWASs in two independent cohorts of 5007 cases and 4579 controls and then a meta-analysis in these newly generated and multiple previously published (2277 cases and 3159 controls) datasets were performed. Three novel and 15 previously reported risk loci were identified from these datasets, increasing the known leprosy risk loci of explained genetic heritability from 23.0 to 38.5%. A comprehensive fine-mapping analysis was conducted, and 19 causal variants and 14 causal genes were identified. Specifically, manual checking of epigenomic information from the Epimap database revealed that the causal variants were mainly located within the immune-relevant or immune-specific regulatory elements. Furthermore, by using gene-set, tissue, and cell-type enrichment analyses, we highlighted the key roles of immune-related tissues and cells and implicated the PD-1 signaling pathways in the pathogenetic mechanism of leprosy. Collectively, our study identified candidate causal variants and elucidated the potential regulatory and coding mechanisms for genes associated with leprosy.
Guidelines for immunological analyses following focused ultrasound treatment
Authors: Frederic Padilla, Jessica Foley, Kelsie Timbie, Timothy N J Bullock, Natasha D Sheybani
Journal: Journal for ImmunoTherapy of Cancer (2023)

Focused ultrasound (FUS) is a powerful emerging tool for non-invasive, non-ionizing targeted destruction of tumors. The last two decades have seen a growing body of preclinical and clinical literature supporting the capacity of FUS to increase nascent immune responses to tumors and to potentiate cancer immunotherapies (e.g. checkpoint inhibitors) through a variety of means, including immune modulation and drug delivery. With the rapid acceleration of this field and a multitude of FUS immunotherapy clinical trials having now been deployed worldwide, there is a need to streamline and standardize the methodology for immunological analyses field-wide. Recently, the Focused Ultrasound Foundation and Cancer Research Institute partnered to convene a group of over 85 leaders to discuss the nexus of FUS and immuno-oncology. The guidelines documented herein were assembled in response to recommendations that emerged from this discussion, emphasizing the urgent need for heightened accessibility of immune analysis methods and standardized protocols unique to the field. These guidelines are designated for existing stakeholders in the FUS immuno-oncology domain or those newly entering the field, to provide guidance on collection, storage, and immunological profiling of tissue or blood specimens in the context of FUS immunotherapy studies, and additionally offer templates for standardized deployment of these methods based on collective experience gained within the field to date. These guidelines are tumor-agnostic and provide evidence-based, consensus-based recommendations for both preclinical and clinical immune analysis of tissue and blood specimens.
CDK5 destabilizes PD-L1 via chaperon-mediated autophagy to control cancer immune surveillance in hepatocellular carcinoma
Authors: Ruonan Zhang, Jie Wang, Yu Du, Ze Yu, Yihan Wang, Yixiao Jiang, Yixin Wu, Ting Le, Ziqi Li, Guoqiang Zhang, Lei Lv, Haijie Ma
Journal: Journal for ImmunoTherapy of Cancer (2023)

Background In the past few years, immunotherapies of hepatocellular carcinoma (HCC) targeting programmed cell death protein 1 (PD-1) and its ligand programmed cell death ligand 1 (PD-L1), have achieved durable clinical benefits. However, only a fraction of HCC patients showed objective clinical response to PD-1/PD-L1 blockade alone. Despite the impact on post-translational modifications of PD-L1 being substantial, its significance in resistance to HCC immunotherapy remains poorly defined. Methods Cyclin-dependent kinase 5 (CDK5) expression was knocked down in HCC cells, CDK5 and PD-L1 protein levels were examined by Western blot. Coimmunoprecipitation was conducted to evaluate the interaction between proteins. Preclinical HCC mice model was constructed to evaluate the effect of CDK5 inhibitor alone or in combination with PD-1 antibody. Clinical HCC samples were used to elucidate the clinical relevance of CDK5, PD-L1, and PD-L1 T290 phosphorylation in HCC. Results We find that CDK5 deficiency upregulates PD-L1 protein expression in HCC cells and decipher a novel molecular mechanism under which PD-L1 is downregulated by CDK5, that is, CDK5 mediated PD-L1 phosphorylation at T290 promotes its binding with chaperon protein heat-shock cognate protein 70 (HSC70) and degradation through chaperon-mediated autophagy. Notably, treatment of CDK5 inhibitor, PNU112455A, effectively upregulates the tumorous PD-L1 level, promotes the response to anti-PD-1 immunotherapy,and prolongs the survival time of mice bearing HCC tumors. What is more, the T290 phosphorylation status of PD-L1 correlates with the prognosis of HCC. Conclusions Targeting CDK5 can synergize with PD-1 blockade to suppress HCC growth, which may have clinical benefits. Our study reveals a unique regulation of the degradation of PD-L1 in HCC, and provides an attractive therapeutic target, a potential drug, and a new prognostic marker for the clinical treatment of HCC.
Low‐dose exercise protects the heart against established myocardial infarction via IGF‐1‐upregulated CTRP9 in male mice
Authors: Yanzhen Tan, Pan Feng, Lele Feng, Lei Shi, Yujie Song, Jian Yang, Weixun Duan, Erhe Gao, Jincheng Liu, Dinghua Yi, Bing Zhang, Yang Sun, Wei Yi
Journal: MedComm (2023)

Regular exercise is recommended as an important component of therapy for cardiovascular diseases in clinical practice. However, there are still major challenges in prescribing an optimized exercise regimen to individual patients with established cardiac disease. Here, we tested the effects of different exercise doses on cardiac function in mice with established myocardial infarction (MI). Exercise was introduced to mice with MI after 4 weeks of surgery. Low-dose exercise (15 min/day for 8 weeks) improved mortality and cardiac function by increasing 44.39% of ejection fractions while inhibiting fibrosis by decreasing 37.74% of distant region. Unlike higher doses of exercise, low-dose exercise consecutively upregulated cardiac expression of C1q complement/tumor necrosis factor-associated protein 9 (CTRP9) during exercise (>1.5-fold). Cardiac-specific knockdown of CTRP9 abolished the protective effects of low-dose exercise against established MI, while cardiac-specific overexpression of CTRP9 protected the heart against established MI. Mechanistically, low-dose exercise upregulated the transcription factor nuclear receptor subfamily 2 group F member 2 by increasing circulating insulin-like growth factor 1 (IGF-1), therefore, upregulating cardiac CTRP9 expression. These results suggest that low-dose exercise protects the heart against established MI via IGF-1-upregulated CTRP9 and may contribute to the development of optimized exercise prescriptions for patients with MI.
Framework humanization optimizes potency of anti-CD72 nanobody CAR-T cells for B-cell malignancies
Authors: William C Temple, Matthew A Nix, Akul Naik, Adila Izgutdina, Benjamin J Huang, Gianina Wicaksono, Paul Phojanakong, Juan Antonio Camara Serrano, Elizabeth P Young, Emilio Ramos, Fernando Salangsang, Veronica Steri, Simayijiang Xirenayi, Michelle Hermiston, Aaron C Logan, Elliot Stieglitz, Arun P Wiita
Journal: Journal for ImmunoTherapy of Cancer (2023)

Approximately 50% of patients who receive anti-CD19 CAR-T cells relapse, and new immunotherapeutic targets are urgently needed. We recently described CD72 as a promising target in B-cell malignancies and developed nanobody-based CAR-T cells (nanoCARs) against it. This cellular therapy design is understudied compared with scFv-based CAR-T cells, but has recently become of significant interest given the first regulatory approval of a nanoCAR in multiple myeloma.
Targeted-release budesonide modifies key pathogenic biomarkers in immunoglobulin A nephropathy: insights from the NEFIGAN trial
Authors: David Wimbury, Masahiro Muto, Jasraj S. Bhachu, Katrin Scionti, Jeremy Brown, Karen Molyneux, Claudia Seikrit, Dita Maixnerová, Laura Pérez-Alós, Peter Garred, Jürgen Floege, Vladimír Tesař, Bengt Fellstrom, Rosanna Coppo, Jonathan Barratt
Journal: Kidney International (2023)

Targeted-release budesonide modifies key pathogenic biomarkers inimmunoglobulin A nephropathy: Insights from the NEFIGAN trial Biomarkers with significant changes from baseline at 9 months with Nefecon 16 mg/d CONCLUSION Nefecon exerts a direct disease-modifying effect in IgAN by targeting the GALT, regulating mucosal immune dysfunction and potentially modulating the systemic immune response
Therapeutic avenues for γδ T cells in cancer
Authors: Gonçalo Palrão Costa, Sofia Mensurado, Bruno Silva-Santos
Journal: Journal for ImmunoTherapy of Cancer (2023)

γδ T cells are regarded as promising effector lymphocytes for next-generation cancer immunotherapies. In spite of being relatively rare in human peripheral blood, γδ T cells are more abundant in epithelial tissues where many tumors develop, and have been shown to actively participate in anticancer immunity as cytotoxic cells or as “type 1” immune orchestrators. A major asset of γδ T cells for tackling advanced cancers is their independence from antigen presentation via the major histocompatibility complex, which clearly sets them apart from conventional αβ T cells. Here we discuss the main therapeutic strategies based on human γδ T cells. These include antibody-based bispecific engagers and adoptive cell therapies, either focused on the Vδ1 + or Vδ2 + γδ T-cell subsets, which can be expanded selectively and differentiated or engineered to maximize their antitumor functions. We review the preclinical data that supports each of the therapeutic strategies under development; and summarize the clinical trials being pursued towards establishing γδ T cell-based treatments for solid and hematological malignancies.
Living kidney donors’ health care needs, experiences, and perspectives across their entire donation trajectory: a semistructured, in-depth interview study
Authors: Katya Loban, Elie Fadel, Peter Nugus, Antoine Przybylak-Brouillard, Heather Badenoch, Jorane-Tiana Robert, Ann Bugeja, Justin Gill, Marie-Chantal Fortin, Charo Rodriguez, Shaifali Sandal
Journal: Kidney International (2023)
Renin and renin blockade have no role in complement activity
Authors: Yuzhou Zhang, Bertha Martin, M. Ashley Spies, Sarah M. Roberts, Joel Nott, Renee X. Goodfellow, Angela F.M. Nelson, Samantha J. Blain, Elena Redondo, Carla M. Nester, Richard J.H. Smith
Journal: Kidney International (2023)

Renin, an aspartate protease, regulates the renin-angiotensin system by cleaving its only known substrate angiotensinogen to angiotensin. Recent studies have suggested that renin may also cleave complement component C3 to activate complement or contribute to its dysregulation. Typically, C3 is cleaved by C3 convertase, a serine protease that uses the hydroxyl group of a serine residue as a nucleophile. Here, we provide seven lines of evidence to show that renin does not cleave C3. First, there is no association between renin plasma levels and C3 levels in patients with C3 Glomerulopathies (C3G) and atypical Hemolytic Uremic Syndrome (aHUS), implying that serum C3 consumption is not increased in the presence of high renin. Second, in vitro tests of C3 conversion to C3b do not detect differences when sera from patients with high renin levels are compared to sera from patients with normal/low renin levels. Third, aliskiren, a renin inhibitor, does not block abnormal complement activity introduced by nephritic factors in the fluid phase. Fourth, aliskiren does not block dysregulated complement activity on cell surfaces. Fifth, recombinant renin from different sources does not cleave C3 even after 24 hours of incubation at 37 ⁰C. Sixth, direct spiking of recombinant renin into sera samples of patients with C3G and aHUS does not enhance complement activity in either the fluid phase or on cell surfaces. And seventh, molecular modeling and docking place C3 in the active site of renin in a position that is not consistent with a productive ground state complex for catalytic hydrolysis. Thus, our study does not support a role for renin in the activation of complement.
Beyond the clinic: the rise of wearables and smartphones in decentralising healthcare
Authors: Conor Wall, Victoria Hetherington, Alan Godfrey
Journal: npj Digital Medicine (2023)

Navigating contemporary healthcare, wearable technology and smartphones are marking the dawn of a transformative era in patient observation and personalised care. Wearables, equipped with various sensing technologies (e.g., accelerometer for movement, optics for heart rate), are increasingly being recognised for their expansive potential in (remote) patient monitoring, diagnostics, and therapeutic applications which suggests a plausible move towards a more decentralised healthcare system. This shift is evident as healthcare providers and patients alike are becoming increasingly accepting of wearable-driven tools, as they enable continuous health monitoring outside of traditional clinical settings. Equally, the ubiquitous nature of smartphones, now more than mere communication tools, is being harnessed to serve as pivotal health monitoring instruments. Their added sensing capabilities with Internet of Things (IoT) driven connectivity enable a (relatively) seamless transition from conventional health practices to a more interconnected, digital age. However, this evolving landscape is not without its challenges, with concerns surrounding data privacy, security, and ensuring equitable access to digital advances. As we delve deeper into digital healthcare, we must harness the full potential of those technologies and ensure their ethical and equitable implementation, envisioning a future where healthcare is not just hospital-centric but is part of our daily lives.
TP-0184 inhibits FLT3/ACVR1 to overcome FLT3 inhibitor resistance and hinder AML growth synergistically with venetoclax
Authors: Anudishi Tyagi, Appalaraju Jaggupilli, Stanley Ly, Bin Yuan, Fouad El-Dana, Venkatesh L. Hegde, Vivek Anand, Bijender Kumar, Mamta Puppala, Zheng Yin, Stephen T. C. Wong, Alexis Mollard, Hariprasad Vankayalapati, Jason M. Foulks, Steven L. Warner, Naval Daver, Gautam Borthakur, V. Lokesh Battula
Journal: Leukemia (2023)
Impact of age and comorbidities on the efficacy and tolerability of bosutinib in previously treated patients with chronic myeloid leukemia: results from the phase 4 BYOND study
Authors: Gianantonio Rosti, Tim H. Brümmendorf, Björn T. Gjertsen, Pilar Giraldo-Castellano, Fausto Castagnetti, Carlo Gambacorti-Passerini, Thomas Ernst, Huadong Zhao, Luke Kuttschreuter, Simon Purcell, Francis J. Giles, Andreas Hochhaus
Journal: Leukemia (2023)

In the phase 4 BYOND trial, patients with pretreated chronic myeloid leukemia (CML) received bosutinib (starting dose: 500 mg/day). Efficacy and safety after ≥3 years of follow-up in 156 patients with Philadelphia chromosome-positive chronic phase CML by age and Charlson Comorbidity Index scores (without the age component; mCCI) is reported. Cumulative major molecular response rates at any time on treatment were 73.6%, 64.5%, and 74.1% in patients <65, 65-74, and ≥75 years of age, and 77.9%, 63.0%, and 59.3% in patients with mCCI scores 2, 3, and ≥4, respectively. Patients <65, 65-74, and ≥75 years of age experienced grade 3/4 treatment-emergent adverse events (TEAEs) at rates of 74.7%, 78.8%, and 96.4% and permanent discontinuations due to AEs at rates of 22.1%, 39.4%, and 46.4%, respectively. In patients with mCCI 2, 3, and ≥4, respective rates of grade 3/4 TEAEs were 77.8%, 77.8%, and 86.7%, and permanent discontinuations due to AEs were 25.3%, 33.3%, and 43.3%. In conclusion, a substantial proportion of patients maintained/achieved cytogenetic and molecular responses across age groups and mCCI scores. Older patients (≥75 years) and those with high comorbidity burden (mCCI ≥4) may require more careful monitoring due to the increased risk of TEAEs. Clinicaltrials.gov: NCT02228382.
Survival benefit of liver resection following complete response to transarterial chemoembolization for intermediate-stage hepatocellular carcinoma: a retrospective, multicenter, cohort study
Authors: Zili Hu, Xiaohui Wang, Yizhen Fu, Dinghua Yang, Zhongguo Zhou, Minshan Chen, Xin Song, Yaojun Zhang
Journal: International Journal of Surgery (2023)

Background: High rate of tumor recurrence jeopardized the long-term survival of hepatocellular carcinoma (HCC) patients with complete response to transarterial chemoembolization (TACE). This study aims to evaluate the survival benefit of liver resection (LR) following the complete response to TACE for intermediate-stage HCC. Methods: A total of 281 intermediate-stage HCC patients with complete response to TACE followed by persistent observation (TACE group) or LR (TLR group) from January 01, 2011 to December 31, 2021 from three institutions in China were included. Overall survival (OS) and disease-free survival (DFS) of patients were compared between the two groups by propensity score–matching (PSM). Results: After PSM, the 1-, 3-, and 5-year OS rates were 91.4%, 71.5%, and 57.1% in the TACE group, and 96.6%, 81.8%, and 72.1% in the TLR group. The 1-, 3-, and 5-year DFS rates were 50.6%, 22.6%, and 6.8% in the TACE group, and 77.3%, 56.3%, and 38.7% in the TLR group. Compared with the TACE group, the TLR group showed significantly longer OS (HR, 0.528; 95%CI, 0.315–0.887; P =0.014) and DFS (HR, 0.388; 95%CI, 0.260–0.580; P &lt;0.001). In patients beyond up-to-7 criterion, no difference was observed with OS (HR, 0.708; 95% CI, 0.354–1.419; P =0.329). LR following the complete response to TACE was safety. Conclusions: This study suggests that intermediate-stage HCC patients could benefit from LR following the complete response to TACE, resulting in longer OS and DFS. In addition, patients beyond up-to-7 could not benefit from the LR treatments.